Patient Name Final Report Date Cancer - Invasive Precision Female 01/01/2099

Pan-Cancer Tissue Date of Birth: 00/00/0000 Case/Specimen ID: AA00-00000 A0 Turnaround: 3 business days Pan-Cancer Tissue#: OR000000000, PCDx-19-00000 Collection Site: R breast Tumor cells: 50% 2 Physician: Dr. Smith Collection Date: 00/00/0000 Specimen size: 8 mm Facility: Some Cancer Treatment Center Received for testing: 00/00/0000 Requirement met: Optimal

1

14 NCCN/FDA indications Therapeutic Option Indicating biomarkers Therapeutic Option Indicating biomarkers

Abemaciclib HR+, HER2 - + PIK3CA mutation, HR + and HER2 - Anastrozole + Fulvestrant ER +, PR + and HER2 - Exemestane ER + PR + Exemestane + Everolimus ER +, PR + and HER2 - Fulvestrant ER + PR + Fulvestrant+Everolimus ER +, PR + and HER2 - Letrozole ER + PR + Letrozole+ Fulvestrant ER +, PR + and HER2 - Megestrol ER + PR + ER+, HER2 - ER+, HER2 - PR + and HER2 - PR + and HER2 - +Everolimus ER +, PR + and HER2 - ER + PR +

Key Biomarker Findings Pan cancer Type specific TMB: Low (8muts/mb) ERBB2 CNV: Not Changed MSI: Stable ERBB2: Wildtype NTRK fusion: Negative ESR1: Wildtype BRCA1: Wildtype PIK3CA: H1047R BRCA2: Wildtype PD- (SP142) IHC: Negative PD-L1 (22C3) Tumor IHC: Negative SAMPLEPD-L1 (22C3) TILs IHC: Negative 8 Additional Therapy Options Bicalutamide Everolimus Flutamide Leuprolide Medroxyprogesterone + Everolimus + ,

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Specimen 4 IHCs AR 3+ 100% Positive PD-L1 (22C3) TILs N/A 0% Negative Tumor cells: 50% PD-L1 (22C3) Tumor CPS: 0 Negative 2 Specimen size: 8 mm PD-L1 (SP142) IC N/A 0% Negative Residual tissue: No TP 2+ 70% Positive

Ulcerated skin involved by infiltrative poorly differentiated ductal carcinoma with not only causes the ulceration but invaded into some adjacent skin

Gross Description: Xxxxxxxx xxxx Xxxxx Xxxxxx Xxxxxxxx Xxxxxxx Xxxtxx xx 0 Xxxxx xxxxxxx xx X00-0000 X0 (xxx XXXx-00-00000) xxxx tx xxxx xxx Xxxxxxxx X&X xxxxx xxxxxxx xx X00-0000 X0 (xxx XXXx-00-00000) xxxxtxxxxx xx xxxxxxxxx tx txx xxxxx xxxxx xxtxxxt xxxxx xx txx xxxxxxxxxxxx xxxxxxxx xxtxxxxxx xxxxxt xxtx xxxxxxxx xxxxxxtxxx xxtx xx 00/00/0000. Xxxxx X00-0000 X0 xxxx xx xxxxxxxx.

Pathologist has performed a comprehensive review of all records and material submitted.

10 pathogenic genomic findings Variant Quantity Gene Variant Quantity CCND1 Amplification 2.03x MYC Amplification 2.55x CDK4 Amplification 2.46x NF2 Q125* 15% MAP3K1 A240Cfs*61 26% PDGFRA V253 13% MAP3K1 H848Qfs*15 28% PIK3CA H1047R 23% MAPK3 Amplification 3.20x SMAD4 Loss 0.59x

3 external results Biomarker Type Value ER IHC Positive High PR IHC Positive HER2 IHC Negative The breast cancer predictive marker (ER, PR, HER2) interpretations in this PCDx test is provided courtesy of an extramural anatomic pathology report and/or provided by the clinical team completing the Exact Sciences tumor analysis requisition/request. The predictive marker data is passed through onto this report and did not arise from ER, PR, HER2 tumor assay performed by Exact Sciences.

26 other genomic findings Note: this table contains all non-reference alleles found in less than 1% of the population. These may be germline or somatic. XXXXTX00 x.0000-0X>X XXXXX X0000X XXXX0 X000 XXT T000X XXXX Xxxx XXX0 X00 XXXX0 X0000T XXXXX0 XXX0X0 X0000T XXX0 Xxxx XX X000X XXX0X0 XXXX0 X0000X X0000X XXX x.0000-0000X>T XXX00X x.000+0000X>X XXXX0X Xxxx T00 XXT0 X000 XXX T000X XXX0XX X000X SAMPLEXXX X0000 XTXX0 x.0000-00000X>X XTXX x.0000+00X>X XXX0 X000 XXXXTX00 X0000 XXXXXX X0000 XTXX X000X XXX0 Xxxx XXXX0 X00 XXX00 Xxxx XXXXX X0000X XX000 X000X XXXXXX X00

22 therapies with potential increased benefit Therapeutic Option Biomarkers NCCN/FDA Level of evidence References HR+, HER2 - Yes I 33,12 Alpelisib + Fulvestrant PIK3CA mutation, HR + and HER2 - Yes I 1,20 Anastrozole + Fulvestrant ER +, PR + and HER2 - Yes II-1 28,29

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22 therapies with potential increased benefit Therapeutic Option Biomarkers NCCN/FDA Level of evidence References Bicalutamide AR + II-3 17 Capecitabine TP + II-3 22 Everolimus ER + II-1 4,2 PIK3CA mutation DTT 23 PR + II-1 2 Exemestane ER + Yes I 3,14 PR + Yes I 3,14 Exemestane + Everolimus ER +, PR + and HER2 - Yes II-1 19,35 Flutamide AR + DTT 13 Fulvestrant ER + Yes II-1 11,37 PR + Yes II-1 11,37 Fulvestrant+Everolimus ER +, PR + and HER2 - Yes II-2 21 Letrozole ER + Yes I 30,24 PR + Yes I 30,24 PIK3CA mutation, ER + and HER2 - I 25 PIK3CA mutation, PR + and HER2 - I 25 Letrozole+ Fulvestrant ER +, PR + and HER2 - Yes I 9 Leuprolide AR + DTT 15 Medroxyprogesterone AR + II-3 7,5 ER + DTT 39 PR + DTT 39 Megestrol ER + Yes I 8,16 PR + Yes I 8,16 Palbociclib ER+, HER2 - Yes I 36 PR + and HER2 - Yes I 36 Pazopanib + Everolimus PIK3CA mutation, ER +, PR + and HER2 - III 31 Ribociclib ER+, HER2 - Yes I 18 PR + and HER2 - Yes I 18 Sorafenib + carboplatin, paclitaxel CCND1 Amplification DTT 38 Tamoxifen+Everolimus ER +, PR + and HER2 - Yes II-1 2 Toremifene ER + Yes I 40,27 PR + Yes I 40,27

4 therapies with potential reduced benefit Therapeutic Option Contraindicating biomarkers References Anastrozole CCND1 Amplification and ER + 26 CCND1 Amplification and PR + 26 PIK3CA mutation 10,34 SMAD4 Loss 6 SAMPLEPIK3CA mutation 10,32

clinical notes

AR expression in breast cancer: Androgen receptor (AR) expression is determined using an anti-human AR AR441; if a minimum of 10% of tumor cell nuclei are immunoreactive, the tumor is considered positive for AR. The androgen receptor functions as a -hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory , translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive (RefSeq, Jan 2017). In hormone receptor positive breast cancer, the androgen receptor (AR) is an emerging prognostic marker and therapeutic target expressed in 60–80% of breast cancers (Kensler et al 2019 PMID: 30795773). In a meta-analysis of 13 studies (n = 5648 patients), tumor AR expression was associated with improved disease-free survival in multivariate analysis, irrespective of hormone receptor status (Bozovic- Spasojevic et al. 2017 PMID: 28151718). Although the current AR IHC at a 10% cutoff for total AR nuclear staining may identify those who would benefit from anti-

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clinical notes androgen therapy, it should be noted that this threshold has been associated with only a modest positive predictive value (PPV) of 30% (Kumar et al. 2017 DOI: 10.1200/PO.17.00075), which may restrict its clinical application.

AURKB in solid tumors: The aurora B (AURKB) gene encodes a member of the subfamily of serine/threonine . These kinases participate in the regulation of alignment and segregation of during mitosis and meiosis through association with [provided by RefSeq, Sep 2015]. The AURKB gene may play an oncogenic role in a broad range of human malignancies by overexpression or gene amplification (Tang et al. 2017 PMID: 28147341, Yan et al. 2016 PMID: 27406026). Recent studies have identified additional functions of Aurora kinases during cancer development, which could suggest that Aurora kinase inhibitors may represent promising targets for future anticancer therapeutics (Yan et al. 2016 PMID: 27406026). Additional lines of evidence support a connection between Aurora kinases and DNA repair and apoptotic pathways (Liu et al. 2013 PMID: 23180582). These findings indicate that both AURKA and AURKB work together to guard against DNA damage, providing a rationale to study potential synergisms between small-molecule inhibitors against Aurora kinases and DNA-damaging agents (Ma and Poon 2020 PMID: 32738522).

CCND1 CNV gain/amplification in breast cancer: The protein encoded by this gene belongs to the highly conserved cyclin family that function as regulators of cyclin-dependent kinases (CDKs). This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of human cancers. [provided by RefSeq, Dec 2019]. CCND1 amplifications are observed in ~5-15% of all breast carcinoma patients (AACR Project GENIE Consortium PMID: 28572459; TCGA PanCancer Atlas PMID: 29625055; COSMIC: the Catalogue of Somatic Mutations in Cancer PMID: 30371878) and are associated with an increased risk of disease recurrence and poor prognosis (Lundgren et al. 2012 PMID: 22475046; Roy et al 2010 PMID: 19904758). In the TransATAC study, which evaluated 1,155 post-menopausal, hormone receptor positive breast cancer patients, CCND1 amplification predicted poor clinical outcome among patients treated with either anastrozole or tamoxifen (Lundgren et al. 2012 PMID: 22475046).

CDK4 CNV gain/amplification: cyclin-dependent kinase 4 amplification occurs in numerous adult malignancies, including breast carcinoma, lymphoma, , and sarcoma, most notably in >95% of well-differentiated and dedifferentiated liposarcomas. In addition, CDK4 is also amplified or overexpressed in pediatric tumor types, such as neuroblastoma. Recent development of a new generation of highly selective small molecule inhibitors targeting CDK4/6 has renewed attention to CDK4/6 inhibition. Three orally bioavailable, selective CDK4/6 inhibitors are approved, including abemaciclib, palbociclib, and ribociclib. Emerging evidence from select case reports suggest that CDK4 copy number gain/amplification may be associated with benefit from palbociclib, for example Dickson et al. 2013 PMID: 24795392.

HR positive, HER2 negative Breast Cancer: Hormone receptor positive breast cancer is defined as a tumor that demonstrates expression of either the or progesterone receptor or both, accounting for the majority of breast cancer cases diagnosed (Carey et al. 2006 PMID: 16757721). The treatments of choice in patients with hormone receptor-positive metastatic breast cancer (HR+ mBC) are endocrine therapies, including, but not limited to selective modulators (SERM), aromatase inhibitors (AI), and selective estrogen receptor degraders (SERD) (Rozeboom et al. 2019 PMID 31911865). While most HR+ breast cancer may initially respond to endocrine treatment, 15–20% of tumors are intrinsically resistant to treatment, and another 30–40% acquire resistance to treatment over a period of many years (Anurag et al. 2018 PMID: 30555626). The resistance that develops in this population of patients may be due to interactions between the hormone receptors, growth factors, and downstream cell-signaling pathways (Lei et al. 2019 PMID: 31839155). Adjuvant may provide additional benefit to HR+ tumors, with decisions regarding the addition of chemotherapy to adjuvant endocrine therapy based on individualized patient and disease factors (Zeidman et al. 2020 PMID: 32740807; Foukakis et al. 2020, https://www.uptodate.com/contents/deciding-when-to-use-adjuvant-chemotherapy-for-hormone- receptor-positive-her2-negative-breast-cancer/).

MAP3K1: Originally described as oncosuppressor genes, preclinical data suggest that MAP3K1 has both tumorigenic and tumor suppressive functions depending on cell type and experimental condition. Transcriptomic analyses have revealed that MAP3K1 mutations associate with a profound deregulation of the MAPK pathway. Mitogen-activated kinase kinase 1, E3 ubiquitin protein (MAP3K1) is a gene that encodes a protein that functions as a serine/ threonine kinase in multiple cascades. Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. MAP3K1 may function as a driver in some cancer types (e.g., melanoma) and is inactivated in other types (e.g., luminal A breast cancer). Recent genome-wide association studies from large consortial studies have led to the discovery of novel breast cancer susceptibility loci in genic (including MAP3K1) and non-genic regions. Recent large-scale genomic studies have revealed that MAP3K1 copy number loss and somatic missense or nonsense mutations are observed in a significant number of different cancers. In breast cancer, MAP3K1 mutations occur almost uniquely in Luminal cancers. MAP3K1 mutations are also observed in HER2+ and triple-negative BC. The presence of MAP3K1 mutations may be tightly associated with an immune-unfavorable phenotype (Hendrickx et al. 2017: PMID: 28344865). MAP3K1 alterations in breast cancer are mutually exclusive with those of MAP2K4 and partially overlap with those of PIK3CA Future studies dissectingSAMPLE the role of involution as a determinant of breast cancer subtype and outcome with regard to MAP3K1 functioning are needed (Pham et al. 2013 PMID: 24386504).

MAPK3 CNV gain/amplification: The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal- regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. MAPK3 Amplification is present in 0.26% of AACR GENIE cases, with breast carcinoma, colorectal adenocarcinoma, non-small cell lung carcinoma, bladder carcinoma, and uterine corpus neoplasm having the greatest prevalence.

Microsatellite Instability Analysis [MSI] Result Stable (MSS): Cancers are classified as either displaying high-frequency microsatellite instability (MSI-H), lowfrequency MSI (MSI-L), or microsatellite stability (MSS) depending on the number of microsatellite loci showing errors. Microsatellite stable cancers (MSS) generally show less immune cell infiltration compared with MSI-H cancers. The greatly increased number of mutation-associated neoantigens resulting from mismatch-repair

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clinical notes deficiency appears to be a key mechanism in the observed responsiveness to anti–PD-1 agents such as (Le et al. 2015; PMID: 26028255).

MYC CNV gain/amplification in Breast Cancer: MYC is regulated at multiple levels, and the protein is a downstream effector of several signaling pathways. Although the relationship between amplification and overexpression is not clearly delineated, in breast cancer MYC amplification appears to be correlated with aggressive tumor phenotypes and poor clinical outcomes. MYC is a marker of proliferation and there is greater interest in evaluating MYC amplification as a biomarker to predict response in clinical trials, some of which may be listed in the appendix of this report.

NF2: The NF2 gene encodes merlin, also known as schwannomin. Merlin helps regulate several key signaling pathways that are important for controlling cell shape, cell growth, and cell adhesion. This protein functions as a tumor suppressor, preventing cells from growing and dividing too fast or in an uncontrolled way. Germline NF2 gene mutations cause neurofibromatosis type 2 (NF2). Somatic mutations in the NF2 gene are involved in the development of several types of tumors, both benign and cancerous. Loss or inactivation of the NF2 gene is often associated with the development of single (isolated) nervous system tumors, including meningiomas, ependymomas, and schwannomas. While these tumors are part of NF2 and schwannomatosis (described above), isolated tumors can develop in individuals who do not have these disorders. NF2 somatic mutations have also been found in multiple cancer types, including but not limited to mesothelioma, anaplastic thyroid cancer, breast cancers, endometrial and liver cancers, in patients not having constitutional NF2 mutations (Dunbar-Schroeder et al. 2014 PMID: 24393766).

PD-L1 (22C3) TILs: PD-L1 is an immune inhibitory receptor ligand that is expressed by immune cells, particularly T-cells and B-cells, as well as various types of tumor cells. Interaction of this ligand with its receptor inhibits T-cell activation and cytokine production. In tumor microenvironments, this interaction provides an immune escape for tumor cells through cytotoxic T-cell inactivation [provided by RefSeq, Sep 2015]. In breast cancer, the rate of PD-L1 positivity in TILs was 33% in a pooled meta-analysis. In the same analysis, PD-L1 expression in immune cells was associated with improved DFS and OS in TNBC (Matikas et al 2019 PMID: 31227501). Expression of PD-L1 (22C3) TILs is determined by evaluating the percentage of PD-L1 expressing tumor-infiltrating immune cells of any intensity. Currently, PD-L1 expression on tumor-infiltrating immune cells appears to be the best predictor of response to + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer whose tumors express PD-L1 stained tumor-infiltrating immune cells [TILs] of any intensity covering ≥ 1% of the tumor area (Schmid et al. 2018 PMID: 30345906). While the PD-L1 (SP142) antibody was used in the referenced study, PD-L1 (22C3) can be used when the specimen is insufficient for evaluation with PD-L1 (SP142). The predictive value of the PD-L1 clone 22C3 for , atezolizumab, avelumab or durvalumab is currently unclear.

PD-L1 (22C3) Tumor negative expression in solid tumors without prescribed companion or complementary diagnostic: For the purpose of PD-L1 reporting, and in lieu of tissue-specific guidelines, oncotypeMAP identifies the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The scoring system divides the results into three groups: those with ≥50% of tumor cells showing any level of positivity (high), those with <50% of tumor cells but ≥1% of tumor cells positive (low), and those with <1% positive (negative). A minimum of 100 viable tumor cells must be present in the PD-L1 stained slide for the specimen to be considered adequate for PD-L1 evaluation. The predictive value of the PD-L1 clone 22C3 for nivolumab, atezolizumab, avelumab or durvalumab is currently unclear. Per the medical literature, there is a strong positive association between PD-L1 expression and response to immune checkpoint inhibitors. However, several studies have revealed that favorable long-term outcomes can be achieved in patients who are PD-L1 negative and this benefit is observable across multiple tumor types and histologies (Patel & Kurzrock 2015 PMID 25695955; Shen and Zhao 2018, PMID 30201790). A recent meta-analysis (Shen and Zhao 2018, PMID 30201790) that included 2000 patients that were PD-L1 negative, revealed that PD-1 or PD-L1 inhibitors were associated with prolonged overall survival and that the favorable overall survival achieved in this patient population is likely due the biological function of the PD-1 or PD-L1 pathway itself and the complicated interaction between cancer cells and the immune system.

PD-L1 (SP142) in breast cancer: PD-L1 is an immune inhibitory receptor ligand that is expressed by immune cells, particularly T-cells and B-cells, as well as various types of tumor cells. Interaction of this ligand with its receptor inhibits T-cell activation and cytokine production. In tumor microenvironments, this interaction provides an immune escape for tumor cells through cytotoxic T-cell inactivation [provided by RefSeq, Sep 2015]. In breast cancer, the rate of PD-L1 positivity in TILs was 33% in a pooled meta-analysis. In the same analysis, PD-L1 expression in immune cells was associated with improved DFS and OS in TNBC (Matikas et al 2019 PMID: 31227501).

PD-L1 (SP142) assay is a qualitative immunohistochemical assay intended for use in the assessment of the PD-L1 protein in triple-negative breast carcinoma (TNBC) tissue (PMA Number P160002 Supplement 009). Evaluation is based on the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity. On March 8, 2019, the Food and Drug Administration granted accelerated approval to atezolizumab (TECENTRIQ, Genentech Inc.) in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) with PD- L1 stained tumor-infiltrating immune cellsSAMPLE [TILs] of any intensity covering ≥ 1% of the tumor area (Schmid et al. 2018 PMID: 30345906). In patients whose tumors express PD-L1, median progression-free survival (PFS) was 7.4 months for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months for those receiving placebo with paclitaxel protein-bound (Schmid et al. 2018 PMID: 30345906).

PDGFRA: Platelet-derived (PDGF) receptors are receptor tyrosine kinases that are required for embryonal development. Two genes, PDGFRA and PDGFRB, encode the receptor a and b isoforms, which are highly homologous and share a common architecture. Activating point mutations in PDGFRA have been described in a small subset of patients with gastrointestinal stromal tumors (GIST) but somatic point mutations in PDGFRA have also been reported in a variety of cancers, including glioblastoma, melanoma, acute myeloid leukemia (AML), peripheral nerve sheath tumors and neuroendocrine carcinoma. Most mutations are located in the juxtamembrane domain or in the activation loop and are likely to disrupt the inhibited conformation of the kinase domain while stabilizing the active one. The most noted alteration is PDGFRA-D842V, which is resistant to , whereas juxtamembrane mutants are highly sensitive to this drug (Velghe et al. 2013 PUBMED 23752188).

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clinical notes

PIK3CA c.3140A>G p.H1047R: A mutation detected in the Kinase Domain (exon 20) of PIK3CA was c.3140A>G p.H1047R. PIK3CA mutations identify patients who are less likely to benefit from anti-HER2 inhibition, especially , alone or in combination. Results from the EMILIA Trial suggest that single- agent T-DM1 may be active in HER2-positive MBC with PIK3CA mutations, which is less sensitive to other standard HER2-directed therapies. Based on data from the phase III SOLAR-1 trial, alpelisib (Piqray) has been approved by the FDA for the treatment of postmenopausal women, and men, with HR-positive, HER2- negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine therapy. Alpelisib has also demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors. However, the data related to efficacy of alpelisib in PIK3CA-altered cancers is largely based on hotspot mutations such as exon 7: C420R; exon 9: E542K; E545A, E545D, E545G, E545K, Q546E, Q546R; and exon 20: H1047L, H1047R, H1047Y). Additionally, numerous PI3K inhibitors have been developed and are in varying stages of clinical testing, with select trials displayed in the clinical trial appendix of this report.

PIK3CA: HR+, HER2 breast bancers with PIK3CA mutations may derive greater benefit from letrozole than tamoxifen; The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptorpositive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years and found that patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (Luen et al. 2018).

SMAD4 CNV loss: SMAD4 is involved in the regulation of cell proliferation, differentiation, migration, and apoptosis. Emerging data suggest a putative relationship between SMAD4 and immune evasion and underscore the clinical importance of SMAD4 as a potential prognostic biomarker. In clinical samples, SMAD4 loss has been associated with worse outcomes and correlates with resistance to chemotherapy.

TMB: Tumor Mutation Burden [TMB] is defined as the total number of DNA mutations per megabase in a tumor sequence. While thresholds for TMB have not been clearly defined for all immunotherapy drugs, and there is at present no consensus for the optimal quantitative or qualitative threshold by cancer type, TMB appears to have an evolving role as a predictive marker for immunotherapy treatment. Overall, a higher TMB is generally associated with longer survival and higher response rates with ICI therapy. While this effect is seen in the majority of cancer types, indicating that TMB underlies fundamental aspects of immune- mediated tumor rejection, the optimal predictive cut-point may vary by histology (Lee et al. 2019 PMID 31361563, Samstein et al 2019 PMID 30643254). For the purpose of TMB stratification, OncotypeMap has adopted the high (≥ 10 mutations per megabase) and low (< 10 mutations per megabase) dichotomy based on the retrospective analysis of TMB in the CheckMate 227 trial, in which NSCLC patients were treated with nivolumab + combination (Hellmann et al. 2018, PMID: 29658845). This cutoff is also the suggested TMB threshold that underlies the recent tissue-agnostic FDA approval for pembrolizumab to treat adult and pediatric patients with unresectable or metastatic solid tumors, who have progressed following prior treatment and who have no satisfactory alternative treatment options.

TP (TYMP): Thymidine phosphorylase (TP, TYMP), also known as ‘‘platelet-derived endothelial cell growth factor’’ (PD-ECGF), is an , which promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. TP not only serves as an indicator of angiogenic potential and as a prognostic factor but may also play an important role in cancer chemotherapy as a target for antiangiogenic agents. Recent works have demonstrated that a manipulation of intracellular TP levels can affect sensitivity to both 5-FU and 5-FU prodrugs , suggesting an important role for the activation of the extensively used 5-fluorouracil prodrug capecitabine. Clinical trials that combine capecitabine with TP- inducing therapies (such as or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in both cancer development as well as therapy. TP inhibitors can abrogate the tumorigenic and metastatic properties of TP and TP activity may be necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy (Bronckaers et al. 2009 PMID 19434693)

clinical trials in tumor type AR +, ER + and HER2 - NCT02955394 Enzalutamide | Fulvestrant Preoperative Fulvestrant With or Without Enzalutamide in ER+/Her2- Breast Cancer BRCA1 WT, BRCA2 WT and NCT02401347 PARP Inhibitor BMN-673 HER2 - Phase II Trial of in BRCA1/2 Wild-typeSAMPLE HER2-negative Breast Cancer and Other Solid Tumors CCND1 Amplification NCT03454529 Simvastatin The Effect of Simvastatin on Breast Cancer Cell Growth in Women With Stage I-II Breast Cancer CCND1 Amplification and NCT03344536 Fulvestrant | Debio 1347 PR + A Study of Debio 1347 Plus Fulvestrant in Patients With Metastatic Breast Cancer AMG 386 | | MK-2206 | T-DM1 | Ganetespib | ABT-888 | | ER + NCT01042379 PLX3397 | Pembrolizumab I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer

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clinical trials ER + NCT02993159 Afimoxifene | Placebo | Tamoxifen Testing an Active Form of Tamoxifen (4-hydroxytamoxifen) Delivered Through the Breast Skin to Control Ductal Carcinoma in Situ (DCIS) of the Breast ER + NCT03294694 Ribociclib | PDR001 | Fulvestrant Ribociclib + PDR001 in Breast Cancer and Ovarian Cancer ER + NCT03332797 GDC-9545 | Palbociclib | LHRH A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor- Positive Breast Cancer ER + NCT03573648 Avelumab | Tamoxifen | Palbociclib Neoadjuvant Endocrine Therapy, Palbociclib, Avelumab in Estrogen Receptor Positive Breast Cancer Mammaglobin-A DNA Vaccine | Anastrozole | Letrozole | Tamoxifen | Exemestane | ER + and HER2 - NCT02204098 Goserelin Safety and Immune Response to a Mammaglobin-A DNA Vaccine In Breast Cancer Patients Undergoing Neoadjuvant Endocrine Therapy ER + and HER2 - NCT02626507 Gedatolisib | Faslodex | Palbociclib | Zoladex Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer ER + and HER2 - NCT02632045 LEE011 | Fulvestrant | Placebo Study of Efficacy of Ribociclib After Progression on CDK4/6 Inhibition in Patients With HR+ HER2- Advanced Breast Cancer ER + and HER2 - NCT02668666 Palbociclib | Tamoxifen Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer ER + and HER2 - NCT02684032 Gedatolisib | Palbociclib | Letrozole | Fulvestrant A Study To Assess The Tolerability And Clinical Activity Of Gedatolisib In Combination With Palbociclib/Letrozole Or Palbociclib/Fulvestrant In Women With Metastatic Breast Cancer ER + and HER2 - NCT02738866 Palbociclib | Fulvestrant Palbociclib With Fulvestrant for Metastatic Breast Cancer After Treatment With Palbociclib and an Aromatase Inhibitor ER + and HER2 - NCT02752685 Pembrolizumab | Nab-Paclitaxel Phase II Study of Pembrolizumab and Nab-paclitaxel in HER-2 Negative Metastatic Breast Cancer ER + and HER2 - NCT02764541 Letrozole | Tamoxifen | Palbociclib | Endocrine Therapy Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study (PELOPS) ER + and HER2 - NCT02778685 Letrozole | Palbociclib | Pembrolizumab Pembrolizumab, Letrozole, and Palbociclib in Treating Postmenopausal Patients With Newly Diagnosed Metastatic Stage IV Estrogen Receptor Positive Breast Cancer ER + and HER2 - NCT03250676 H3B-6545 Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer ER + and HER2 - NCT03366844 Pembrolizumab | Radiation Breast Cancer Study of Preoperative Pembrolizumab + Radiation ER + and HER2 - NCT03439735 Aromatase Inhibitor and Palbociclib Determinants of Resistance to First-line Therapy With an AI and Palbociclib for HR+ MBC ER + and HER2 - NCT03455270 G1T48 G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer ER + and HER2 - NCT03471663 D-0502 | palbociclib A First-in-Human Study of D-0502 Alone and inSAMPLE Combination With Palbociclib in Women With Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer ER + and HER2 - NCT03560531 ZN-c5 | Palbociclib A Study of ZN-c5 in Subjects With Breast Cancer ER + and HER2 - NCT03659136 Xentuzumab | Placebo | Everolimus | Exemestane The XENERA™ 1 Study Tests Xentuzumab in Combination With Everolimus and Exemestane in Women With Hormone Receptor Positive and HER2-negative Breast Cancer That Has Spread ER + and HER2 - NCT03691493 Anastrozole | Exemestane | Fulvestrant | Letrozole | Palbociclib | Tamoxifen Radiation Therapy, Palbociclib, and Hormone Therapy in Treating Breast Cancer Patients With Bone Metastasis ER + and HER2 - NCT03701334 Ribociclib | Endocrine Therapy A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer

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clinical trials Pembrolizumab | Placebo | Paclitaxel | | | | ER + and HER2 - NCT03725059 Endocrine therapy Study of Pembrolizumab (MK-3475) Versus Placebo in Combination With Neoadjuvant Chemotherapy & Adjuvant Endocrine Therapy in the Treatment of Early-Stage Estrogen Receptor- Positive, Human Epidermal 2-Negative (ER+/HER2-) Breast Cancer (MK-3475-756/KEYNOTE-756) Nivolumab | Doxorubicin +Cyclophosphamide | Nivolumab + ER + and HER2 - NCT03742986 +Trastuzumab + | Doxorubicin+Cyclophosphamide Trial of Nivolumab With Chemotherapy as Neoadjuvant Treatment in Inflammatory Breast Cancer (IBC) ER + and HER2 - NCT03747042 Letrozole Letrozole in Post-Menopausal Patients With Operable Hormone-Sensitive Breast Cancer ER + and HER2 - NCT03803761 | Fulvestrant A Study of a New Drug Combination, Copanlisib and Fulvestrant, in Advanced Breast Cancer ER + and HER2 - NCT03822468 Ribociclib | Letrozole or Anastrozole | Goserelin Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer ER + and HER2 - NCT03854903 Palbociclib | | Fulvestrant WI231696: Bosutinib, Palbocicilib and Fulvestrant for HR+HER2- Advanced Breast Cancer Refractory to a CDK4/6 Inhibitor ER + and HER2 - NCT03901339 ||Capecitabine|| Study of IMMU-132 in HR+/HER2- MBC (TROPICS-02) ER + and HER2 - NCT03906669 Letrozole|Letrozole and Prometrium|Tamoxifen and Prometrium A Window of Opportunity Study of Pre-operative Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Breast Hormone Receptor Positive (HR+) Human Epidermal Receptor 2 Negative (HER2-) Breast Cancer. ER + and HER2 - NCT03939897 Abemaciclib|Copanlisib|Fulvestrant Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer ER +, HER2 - and PIK3CA NCT01723774 PD0332991 | Anastrozole mutation PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer ER +, PR + and HER2 - NCT03519178 PF-06873600 A Safety, Pharmacokinetic, Pharmacodynamic and Anti-Tumor Study of PF-06873600 as a Single Agent and in Combination With Endocrine Therapy AMG 386 | Ganitumab | MK-2206 | T-DM1 | Ganetespib | ABT-888 | Neratinib | HER2 - NCT01042379 PLX3397 | Pembrolizumab I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer HER2 - NCT01750073 Paclitaxel | Cyclophosphamide | Trastuzumab | Doxorubicin Paclitaxel and Cyclophosphamide With or Without Trastuzumab Before Surgery in Treating Patients With Previously Untreated Breast Cancer HER2 - NCT02157051 CD105/Yb-1/SOX2/CDH3/MDM2 multiplasmid vaccine Vaccine Therapy in Treating Patients With HER2-Negative Stage III-IV Breast Cancer HER2 - NCT02957968 Doxorubicin | Cyclophosphamide | Paclitaxel | Carboplatin Neoadjuvant Pembrolizumab + Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca HER2 - NCT03294694 Ribociclib | PDR001 | Fulvestrant Ribociclib + PDR001 in Breast Cancer and Ovarian Cancer Anastrozole | Exemestane | Fulvestrant | Letrozole | Paclitaxel | Talimogene HER2 - NCT03554044SAMPLE Laherparepvec | Tamoxifen T-VEC With Chemotherapy or Endocrine Therapy in Treating Participants With Metastatic, Unresectable, or Locoregionally Recurrent HER2- Negative Breast Cancer (DS-8201a) | Capecitabine | Eribulin | Gemcitabine | HER2 - NCT03734029 Paclitaxel | Nab-paclitaxel Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04] PIK3CA mutation NCT03337724 Ipatasertib | Paclitaxel | Placebo A Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Participants With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor-Positive, HER2-Negative Breast Cancer

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clinical trials PIK3CA mutation, ER + and NCT02738866 Palbociclib | Fulvestrant HER2 - Palbociclib With Fulvestrant for Metastatic Breast Cancer After Treatment With Palbociclib and an Aromatase Inhibitor AMG 386 | Ganitumab | MK-2206 | T-DM1 | Ganetespib | ABT-888 | Neratinib | PR + NCT01042379 PLX3397 | Pembrolizumab I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer PR + and HER2 - NCT02738866 Palbociclib | Fulvestrant Palbociclib With Fulvestrant for Metastatic Breast Cancer After Treatment With Palbociclib and an Aromatase Inhibitor PR + and HER2 - NCT02752685 Pembrolizumab | Nab-Paclitaxel Phase II Study of Pembrolizumab and Nab-paclitaxel in HER-2 Negative Metastatic Breast Cancer PR + and HER2 - NCT02764541 Letrozole | Tamoxifen | Palbociclib | Endocrine Therapy Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study (PELOPS) PR + and HER2 - NCT03439735 Aromatase Inhibitor and Palbociclib Determinants of Resistance to First-line Therapy With an AI and Palbociclib for HR+ MBC PR + and HER2 - NCT03659136 Xentuzumab | Placebo | Everolimus | Exemestane The XENERA™ 1 Study Tests Xentuzumab in Combination With Everolimus and Exemestane in Women With Hormone Receptor Positive and HER2-negative Breast Cancer That Has Spread PR + and HER2 - NCT03659136 Xentuzumab | Placebo | Everolimus | Exemestane The XENERA™ 1 Study Tests Xentuzumab in Combination With Everolimus and Exemestane in Women With Hormone Receptor Positive and HER2-negative Breast Cancer That Has Spread PR + and HER2 - NCT03691493 Anastrozole | Exemestane | Fulvestrant | Letrozole | Palbociclib | Tamoxifen Radiation Therapy, Palbociclib, and Hormone Therapy in Treating Breast Cancer Patients With Bone Metastasis PR + and HER2 - NCT03701334 Ribociclib | Endocrine Therapy A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer Nivolumab | Doxorubicin +Cyclophosphamide | Nivolumab + Docetaxel PR + and HER2 - NCT03742986 +Trastuzumab +Pertuzumab | Doxorubicin+Cyclophosphamide Trial of Nivolumab With Chemotherapy as Neoadjuvant Treatment in Inflammatory Breast Cancer (IBC) PR + and HER2 - NCT03822468 Ribociclib | Letrozole or Anastrozole | Goserelin Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer PR + and HER2 - NCT03854903 Palbociclib | Bosutinib | Fulvestrant WI231696: Bosutinib, Palbocicilib and Fulvestrant for HR+HER2- Advanced Breast Cancer Refractory to a CDK4/6 Inhibitor PR + and HER2 - NCT03901339 Sacituzumab Govitecan|Eribulin|Capecitabine|Gemcitabine|Vinorelbine Study of IMMU-132 in HR+/HER2- MBC (TROPICS-02) PR + and HER2 - NCT03906669 Letrozole|Letrozole and Prometrium|Tamoxifen and Prometrium A Window of Opportunity Study of Pre-operative Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Breast Hormone Receptor Positive (HR+) Human Epidermal Receptor 2 Negative (HER2-) Breast Cancer. PR + and HER2 - NCT03939897 Abemaciclib|Copanlisib|Fulvestrant Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer multi-indication trials CCND1 Amplification NCT02896335SAMPLEPalbociclib Palbociclib In Progressive Brain Metastases CCND1 Amplification NCT03310879 Abemaciclib Study of the CDK4/6 Inhibitor Abemaciclib in Solid Tumors Harboring Genetic Alterations in Genes Encoding D-type Cyclins or Amplification of CDK4 or CDK6 CDK4 Amplification NCT02693535 Palbociclib TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer CDK4 Amplification NCT02896335 Palbociclib Palbociclib In Progressive Brain Metastases

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clinical trials CDK4 Amplification NCT03310879 Abemaciclib Study of the CDK4/6 Inhibitor Abemaciclib in Solid Tumors Harboring Genetic Alterations in Genes Encoding D-type Cyclins or Amplification of CDK4 or CDK6 CDK4 Amplification NCT03237390 Gemcitabine | Ribociclib Ribociclib and Gemcitabine Hydrochloride in Treating Patients With Advanced or Metastatic Solid Tumors ER + and HER2 - NCT03959891 Ipatasertib;Fulvestrant;Aromatase Inhibitor;Palbociclib; AKT Inhibitor, Ipatasertib, With Endocrine and CDK 4/6 Inhibitor for Patients With Metastatic Breast Cancer (TAKTIC) ER + and HER2 - NCT04109066 paclitaxel (PTX);;cyclophosphamide;Endocrine Therapy; Study of Nivolumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in Participants With High-risk, Estrogen Receptor-Positive (ER+), Human Receptor 2-Negative (HER2-) Primary Breast Cancer ER + and HER2 - NCT04305834 Abemaciclib; Abemaciclib Monotherapy in Treating Older Patients With Hormone Receptor Positive Metastatic Breast Cancer ER + and HER2 - NCT04305496 Fulvestrant;Capivasertib;Placebo; Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer ER + and HER2 - NCT04305236 Abemaciclib;Fulvestrant; Neo-Adjuvant Abemaciclib With Fulvestrant in Patients With ER/PR +HER Negative Breast Cancer ER + and HER2 - NCT04294225 Anastrozole;Letrozole; Anastrozole and Letrozole After Surgery for the Treatment of Stage I-III Breast Cancer ER + and HER2 - NCT04352777 Abemaciclib;Fulvestrant;Aromatase Inhibitors; Impact of Endocrine Therapy and Abemaciclib on Host and Tumor Immune Cell Repertoire/Function in Advanced ER+/HER2- Breast Cancer ER + and HER2 - NCT04443348 Pembrolizumab;Paclitaxel;Carboplatin;Cyclophosphamide;Doxorubicin;Capecitabine; Pre-op Pembro + Radiation Therapy in Breast Cancer ER + and HER2 - NCT04514159 ZN-c5;Abemaciclib; A Study of ZN-c5 and Abemaciclib in Participants With Breast Cancer ER + and HER2 - NCT03032406 Hydroxychloroquine;Everolimus; CLEVER Pilot Trial: A Phase II Pilot Trial of HydroxyChLoroquine, EVErolimus or the Combination for Prevention of Recurrent Breast Cancer ER + and HER2 - NCT03616587 AZD9833;AZD9833 with palbociclib/everolimus Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer ER + and HER2 - NCT04568616 Letrozole 2.5mg; Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI) ER +, PR + and HER2 + NCT04553770 Anastrozole; Trastuzumab Deruxtecan Alone or in Combination With Anastrozole for the Treatment of Early Stage HER2 Low, Hormone Receptor Positive Breast Cancer ER +, PR + and HER2 - NCT04052555 Berzosertib; Testing the Addition of an Anti-cancer Drug, Berzosertib, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer ER +, PR + and HER2 - NCT04215146 Paclitaxel;Avelumab; A Study to Assess Overall Response Rate by Inducing an Inflammatory Phenotype in Metastatic BReast cAnCEr With the Oncolytic Reovirus PeLareorEp in CombinaTion With Anti-PD-L1 Avelumab and Paclitaxel - BRACELET-1 Study ER +, PR + and HER2 - NCT04134884 Talazoparib;ASTX727; Study of ASTX727 Plus Talazoparib in PatientsSAMPLE With Triple Negative or Hormone Resistant/HER2-negative Metastatic Breast Cancer ER +, PR + and HER2 - NCT03147287 Palbociclib;Fulvestrant;Avelumab; Palbociclib After CDK and Endocrine Therapy (PACE) ER +, PR + and HER2 - NCT04563507 Letrozole 2.5Mg Tab;Palbociclib 125mg; Combined Immunotherapies in Metastatic ER+ Breast Cancer ER +, PR + and HER2 - NCT04557449 PF-07220060; Study to Test the Safety and Tolerability of PF-07220060 in Participants With Advance Solid Tumors

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clinical trials PF-07104091 monotherapy;PF-07104091 + palbociclib;PF-07104091 + palbociclib + ER +, PR + and HER2 - NCT04553133 letrozole; PF-07104091 as a Single Agent and in Combination Therapy ER +, PR + and HER2 - NCT04305496 Fulvestrant;Capivasertib;Placebo; Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer HER2 - NCT03952325 Tesetaxel;Tesetaxel;Tesetaxel;Nivolumab;Pembrolizumab;Atezolizumab;Tesetaxel; Tesetaxel Plus 3 Different PD-(L)1 Inhibitors in Patients With Triple-Negative MBC and Tesetaxel Monotherapy in Patients With HER2-Negative MBC HER2 - NCT04042480 SGN-CD228A; A Study of SGN-CD228A in Advanced Solid Tumors HER2 - NCT04333706 Capecitabine; A Dose Finding Phase 1 of Sarilumab Plus Capecitabine in HER2/Neu-Negative Metastatic Breast Cancer and a Single-arm, Historically-controlled Phase 2 Study of Sarilumab Plus Capecitabine in Stage I-III Triple Negative Breast Cancer With High-Risk Residual Disease (EMPOWER) HER2 - and ER + NCT04494425 Trastuzumab deruxtecan;Capecitabine;Paclitaxel;Nab-Paclitaxel; Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer HER2 - and ER + NCT04494425 Trastuzumab deruxtecan;Capecitabine;Paclitaxel;Nab-Paclitaxel; Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer MAP3K1 mutation NCT02857270 LY3214996 | Midazolam | Abemaciclib | Nab-paclitaxel | Gemcitabine A Study of LY3214996 Administered Alone or in Combination With Other Agents in Participants With Advanced/Metastatic Cancer MAPK3 Amplification NCT03520075 ASTX029 Study of ASTX029 in Subjects With Advanced Solid Tumors MSI Stable NCT03711058 Copanlisib | Nivolumab Study of PI3Kinase Inhibition (Copanlisib) and Anti-PD-1 Antibody Nivolumab in Relapsed/Refractory Solid Tumors With Expansions in Mismatch-repair Proficient (MSS) MYC Amplification NCT02873975 LY2606368 A Study of LY2606368 (Prexasertib) in Patients With Solid Tumors With Replicative Stress or Homologous Repair Deficiency MYC Amplification NCT03718091 M6620 M6620 (VX-970) in Selected Solid Tumors PD-L1 (SP142) IC - NCT04468061 Sacituzumab Govitecan;Pembrolizumab; Sacituzumab Govitecan +/- Pembrolizumab in Metastatic TNBC PDGFRA mutation NCT02272998 Ponatinib for Patients Whose Advanced Solid Tumor Cancer Has Activating Mutations Involving the Following Genes: FGFR1, FGFR2, FGFR3, FGFR4, RET, KIT. PDGFRA mutation NCT02693535 TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer PIK3CA mutation NCT03842228 Copanlisib | Durvalumab | Testing the Combination of the Anti-cancer Drugs Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumors With Selected Mutations PIK3CA mutation NCT04317105 Copanlisib Hydrochloride; Testing the Addition of an Anti-cancer Drug, Copanlisib, to the Usual Immunotherapy (Nivolumab With or Without Ipilimumab) in Patients With Advanced Solid Cancers That Have Changes in the Following Genes: PIK3CA and PTEN ;GDC-0077;;Ipatasertib;Atezolizumab;Trastuzumab PIK3CA mutation NCT04632992SAMPLEEmtansine;Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf;;Investigator's Choice of Chemotherapy; A Study Evaluating Targeted Therapies in Participants Who Have Advanced Solid Tumors With Genomic Alterations or Protein Expression Patterns Predictive of Response PR + and HER2 - NCT03959891 Ipatasertib;Fulvestrant;Aromatase Inhibitor;Palbociclib; AKT Inhibitor, Ipatasertib, With Endocrine and CDK 4/6 Inhibitor for Patients With Metastatic Breast Cancer (TAKTIC) PR + and HER2 - NCT04305834 Abemaciclib; Abemaciclib Monotherapy in Treating Older Patients With Hormone Receptor Positive Metastatic Breast Cancer PR + and HER2 - NCT04305496 Fulvestrant;Capivasertib;Placebo; Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer

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clinical trials PR + and HER2 - NCT04305236 Abemaciclib;Fulvestrant; Neo-Adjuvant Abemaciclib With Fulvestrant in Patients With ER/PR +HER Negative Breast Cancer PR + and HER2 - NCT04294225 Anastrozole;Letrozole; Anastrozole and Letrozole After Surgery for the Treatment of Stage I-III Breast Cancer RAS WT, BRAF WT NCT02693535 Cetuximab TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer TP53 WT NCT03449381 BI 907828 This Study Aims to Find the Best Dose of BI 907828 in Patients With Different Types of Advanced Cancer (Solid Tumors) TP53 WT NCT03560882 Atorvastatin A Pilot Trial of Atorvastatin in Tumor Protein 53 (p53) -Mutant and p53 Wild-Type Malignancies TP53 WT NCT03725436 MDM2/MDMX Inhibitor ALRN-6924 | Paclitaxel ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors

genes negative for small variants ABCB1 ABCC1 ABCC2 ABL1 ACVR1 ACVR1B ACVR2A ACVR2B ACVRL1 ADAMTS1 ADAMTS16 ADAMTS18 ADAMTS6 ADAMTS9 ADAMTSL1 AKT1 AKT2 AKT3 ALK AMER1 APC APLNR AR ARAF AREG ARID1A ARID1B ARID2 ATM ATR ATRX AURKA AURKB AXIN1 AXL B2M BAP1 BARD1 BCOR BMP6 BMPR1A BMPR1B BNIP3 BRAF BRCA1 BRCA2 BRIP1 BTK BUB1B CALR CBL CCND1 CCND2 CCND3 CCNE1 CD274 CDA CDC73 CDH1 CDK12 CDK4 CDK6 CDKN2A CHEK1 CHEK2 CHFR CHKA CIC CREBBP CSF1R CTLA4 CTNNB1 CYP19A1 CYP1A1 CYP2D6 CYP3A4 CYSLTR2 dCK DDR2 DICER1 DNMT3A EGFR EMSY EP300 EPCAM EPHA5 EPHA7 ERBB2 ERBB3 ERBB4 ERCC1 ERCC2 ERCC3 ERRFI1 ESR1 ESR2 EWSR1 EZH2 FAM175A FANCA FANCC FANCD2 FANCE FANCF FANCG FANCM FAT1 FBXW7 FCGR2A FGD4 FGF3 FGF4 FGFR1 FGFR2 FGFR3 FGFR4 FLT3 FLT4 FOXL2 FUBP1 GAS6 GATA3 GLI1 GNA11 GNAQ GNAS GSTP1 HAMP HDAC2 HGF HNF1A HRAS HSD3B1 IDH1 IDH2 IGF1R IKZF1 IL6R JAK1 JAK2 JAK3 KDM5C KDM6A KDR KEAP1 KIT KRAS MAF MAP2K1 MAP2K2 MAPK1 MAPK3 MAPKAPK5 MDM2 MDM4 MED12 MEN1 MET MGMT MLH1 MPL MRE11A MSH2 MSH6 MTHFR MTOR MUTYH MYC MYCN MYOD1 NBN NF1 NFE2L2 NOTCH1 NOTCH2 NOTCH3 NPM1 NRAS NTRK1 NTRK2 NTRK3 PALB2 PBRM1 PDCD1LG2 PDGFRB PIK3CB PIK3CD PIK3CG PIK3R1 PIM1 PLCB4 PLCG1 PMS2 POLD1 POLE PPP2R1A PTCH1 PTEN PTPN11 RAD50 RAD51C RAD51D RAF1 RB1 RBM10 RECQL RET RHEB RICTOR RIT1 RNF43 ROS1 RPTOR RRM1 SDHB SDHC SETD2 SF3B1 SMAD1 SMAD2 SMAD4 SMAD5 SMAD9 SMARCA4 SMARCB1 SMO SOCS1 SPOP STAG2 STAT3 STAT5A STAT5B STK11 SUFU TERT-p TGFB1 TGFB2 TGFB3 TGFBR1 TGFBR2 TNFAIP3 TNK1 TOP2A TP53 TSC1 TSC2 TSHR TYMS VEGFA VHL WT1 XRCC1 YES1

genes negative for fusions and structural variants ALK BRAF EGFR FGFR1 FGFR2 FGFR3 MET RET ROS1 NTRK1 NTRK2 ETV6-NTRK3 genesSAMPLE negative for copy number variants (amplifications) ABCB1 ABCC1 ABCC2 ABL1 ACVR1 ACVR1B ACVR2A ACVR2B ACVRL1 ADAMTS1 ADAMTS16 ADAMTS18 ADAMTS6 ADAMTS9 ADAMTSL1 AKT1 AKT2 AKT3 ALK AMER1 APC APLNR AR ARAF AREG ARID1A ARID1B ARID2 ATM ATR ATRX AURKA AURKB AXIN1 AXL B2M BAP1 BARD1 BCOR BMP6 BMPR1A BMPR1B BNIP3 BRAF BRCA1 BRCA2 BRIP1 BTK BUB1B CALR CBL CCND2 CCND3 CCNE1 CD274 CDA CDC73 CDH1 CDK12 CDK6 CDKN2A CHEK1 CHEK2 CHFR CHKA CIC CREBBP CSF1R CTLA4 CTNNB1 CYP19A1 CYP1A1 CYP2D6 CYP3A4 CYSLTR2 dCK DDR2 DICER1 DNMT3A EGFR EMSY EP300 EPCAM EPHA5 EPHA7 ERBB2 ERBB3 ERBB4 ERCC1 ERCC2 ERCC3 ERRFI1 ESR1 ESR2 EWSR1 EZH2 FAM175A FANCA FANCC FANCD2

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genes negative for copy number variants (amplifications) FANCE FANCF FANCG FANCM FAT1 FBXW7 FCGR2A FGD4 FGF3 FGF4 FGFR1 FGFR2 FGFR3 FGFR4 FLT3 FLT4 FOXL2 FUBP1 GAS6 GATA3 GLI1 GNA11 GNAQ GNAS GSTP1 HAMP HDAC2 HGF HNF1A HRAS HSD3B1 IDH1 IDH2 IGF1R IKZF1 IL6R JAK1 JAK2 JAK3 KDM5C KDM6A KDR KEAP1 KIT KRAS MAF MAP2K1 MAP2K2 MAP3K1 MAPK1 MAPKAPK5 MDM2 MDM4 MED12 MEN1 MET MGMT MLH1 MPL MRE11A MSH2 MSH6 MTHFR MTOR MUTYH MYCN MYOD1 NBN NF1 NF2 NFE2L2 NOTCH1 NOTCH2 NOTCH3 NPM1 NRAS NTRK1 NTRK2 NTRK3 PALB2 PBRM1 PDCD1LG2 PDGFRA PDGFRB PIK3CA PIK3CB PIK3CD PIK3CG PIK3R1 PIM1 PLCB4 PLCG1 PMS2 POLD1 POLE PPP2R1A PTCH1 PTEN PTPN11 RAD50 RAD51C RAD51D RAF1 RB1 RBM10 RECQL RET RHEB RICTOR RIT1 RNF43 ROS1 RPTOR RRM1 SDHB SDHC SETD2 SF3B1 SMAD1 SMAD2 SMAD5 SMAD9 SMARCA4 SMARCB1 SMO SOCS1 SPOP STAG2 STAT3 STAT5A STAT5B STK11 SUFU TERT-p TGFB1 TGFB2 TGFB3 TGFBR1 TGFBR2 TNFAIP3 TNK1 TOP2A TP53 TSC1 TSC2 TSHR TYMS VEGFA VHL WT1 XRCC1 YES1

references

1. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, 2. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of Hormone Receptor-Positive Advanced Breast Cancer. N Engl J everolimus in combination with tamoxifen in patients with hormone receptor- Med. 2019;380(20):1929-40. positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718-24.

3. Bartlett JM, Brookes CL, Robson T, et al. Estrogen receptor and 4. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal progesterone receptor as predictive biomarkers of response to endocrine hormone-receptor-positive advanced breast cancer. N Engl J Med. therapy: a prospectively powered pathology study in the Tamoxifen and 2012;366(6):520-9. Exemestane Adjuvant Multinational trial. J Clin Oncol. 2011;29(12):1531-8.

5. Birrell SN, Roder DM, Horsfall DJ, Bentel JM, Tilley WD. 6. Boulay JL, Mild G, Lowy A, et al. SMAD4 is a predictive marker for 5- Medroxyprogesterone acetate therapy in advanced breast cancer: the fluorouracil-based chemotherapy in patients with colorectal cancer. Br J predictive value of androgen receptor expression. J Clin Oncol. 1995;13(7): Cancer. 2002;87(6):630-4. 1572-7.

7. Buchanan G, Birrell SN, Peters AA, et al. Decreased androgen receptor 8. Buzdar A, Douma J, Davidson N, et al. Phase III, multicenter, double-blind, levels and receptor function in breast cancer contribute to the failure of randomized study of letrozole, an aromatase inhibitor, for advanced breast response to medroxyprogesterone acetate. Cancer Res. 2005;65(18): cancer versus megestrol acetate. J Clin Oncol. 2001;19(14):3357-66. 8487-96.

9. Copur M. Letrozole and Fulvestrant Combination in Second Line or More for 10.De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S. KRAS, BRAF, Estrogen Receptor Positive Metastatic Breast Cancer; Efficacy andPredictive PIK3CA, and PTEN mutations: implications for targeted therapies in Factors of Response. Published online 2011 metastatic colorectal cancer. Lancet Oncol. 2011;12(6):594-603.

11.Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III 12.Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A Phase II Study of trial comparing fulvestrant 250 mg with fulvestrant 500 mg in Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with postmenopausal women with estrogen receptor-positive advanced breast Refractory HR+/HER2- Metastatic Breast Cancer. Clin Cancer Res. cancer. J Clin Oncol. 2010;28(30):4594-600. 2017;23(17):5218-24.. 13.El Sheikh SS, Romanska HM, Abel P,SAMPLE Domin J, Lalani el-N. Predictive value of 14.Fallowfield LJ, Kilburn LS, Langridge C, et al. Long-term assessment of quality PTEN and AR coexpression of sustained responsiveness to hormonal therapy of life in the Intergroup Exemestane Study: 5 years post-randomisation. Br J in prostate cancer--a pilot study. Neoplasia. 2008;10(9):949-53. Cancer. 2012;106(6):1062-7.

15.Fushimi C, Tada Y, Takahashi H, et al. A prospective phase II study of 16.Gill PG, Gebski V, Snyder R, et al. Randomized comparison of the effects of combined androgen blockade in patients with androgen receptor-positive tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on metastatic or locally advanced unresectable salivary gland carcinoma. Ann treatment response and survival in patients with metastatic breast cancer. Ann Oncol. 2018;29(4):979-984. Oncol. 1993;4(9):741-4.

Final Report Paradigm, an Exact Sciences company Laboratory Director: 1-844-232-4719 445 N 5th St., Phoenix, AZ 85004 Joshua Routh, MD Page 13 of 16 Continued CLIA# 03D2082339 Patient Name Final Report Date Breast Cancer - Invasive Precision Female 01/01/2099

references

17.Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients 18.Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy with androgen receptor-positive, estrogen receptor-negative metastatic for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375(18): Breast Cancer. Clin Cancer Res. 2013;19(19):5505-12. 1738-48.

19.Jerusalem G, De Boer RH, Hurvitz S, et al. Everolimus Plus Exemestane vs 20.Juric D, Janku F, Rodón J, et al. Alpelisib Plus Fulvestrant in PIK3CA-Altered Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized A Phase 1b Clinical Trial. JAMA Oncol. 2019;5(2):e184475. Clinical Trial. JAMA Oncol. 2018;4(10):1367-1374.

21.Kornblum N, Zhao F, Manola J, et al. Randomized Phase II Trial of 22.Lee SJ, Choi YL, Park YH, et al. Thymidylate synthase and thymidine Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With phosphorylase as predictive markers of capecitabine monotherapy in patients Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2– with anthracycline- and -pretreated metastatic breast cancer. Cancer Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Chemother Pharmacol. 2011;68(3):743-51. Results of PrE. J Clin Oncol. Published online 2018:JCO.2017.76.933.

23.Lim SM, Park HS, Kim S, et al. Next-generation sequencing reveals somatic 24.Llombart-Cussac A, Guerrero Á, Galán A, et al. Phase II trial with letrozole to mutations that confer exceptional response to everolimus. Oncotarget. maximum response as primary systemic therapy in postmenopausal patients 2016;7(9):10547-56. with ER/PgR[+] operable breast cancer. Clin Transl Oncol. 2012;14(2):125-31.

25.Luen SJ, Asher R, Lee CK, et al. Association of Somatic Driver Alterations 26.Lundgren K, Brown M, Pineda S, et al. Effects of cyclin D1 gene amplification With Prognosis in Postmenopausal, Hormone Receptor-Positive, HER2- and protein expression on time to recurrence in postmenopausal breast Negative Early Breast Cancer: A Secondary Analysis of the BIG 1-98 cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Randomized Clinical Trial. JAMA Oncol. 2018;4(10):1335-43. Breast Cancer Res. 2012;14(2):R57.

27.Mao C, Yang ZY, He BF, et al. Toremifene versus tamoxifen for advanced 28.Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and breast cancer. Cochrane Database Syst Rev. 2012;(7):CD008926. fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435-44.

29.Mehta RS, Barlow WE, Albain KS, et al. Overall Survival with Fulvestrant plus 30.Regan MM, Neven P, Giobbie-Hurder A, et al. Assessment of letrozole and Anastrozole in Metastatic Breast Cancer. N Engl J Med. 2019;380(13): tamoxifen alone and in sequence for postmenopausal women with steroid 1226-1234. hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011;12(12):1101-8.

31.Rodrigues HV, Ke D, Lim J, et al. Phase I combination of pazopanib and 32.Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal everolimus in PIK3CA mutation positive/PTEN loss patients with advanced cancer are associated with clinical resistance to EGFR-targeted monoclonal solid tumors refractory to standard therapy. Invest New Drugs. 2015;33(3): antibodies. Cancer Res. 2009;69(5):1851-7. 700-9.

33.Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in 34.Spindler KL, Pallisgaard N, Lindebjerg J, Frifeldt SK, Jakobsen A. EGFR Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast related mutational status and association to clinical outcome of third-line Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin cetuximab- in metastatic colorectal cancer. BMC Oncol. 2017;35(25):2875-84. Cancer. 2011;11:107.

35.Tesch H, Stoetzer O, Decker T, et al. Efficacy and safety of everolimus plus 36.Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor-Positive exemestane in postmenopausal women with hormone receptor-positive, Advanced Breast Cancer. N Engl J Med. 2015;373(3):209-19. human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial. Int J Cancer. 2019;144(4):877-885.

37.Valachis A, Mauri D, Polyzos NP, Mavroudis D, Georgoulias V, Casazza G. 38.Wilson MA, Zhao F, Khare S, et al. Copy Number Changes Are Associated Fulvestrant in the treatment of advancedSAMPLE breast cancer: a systematic review with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in and meta-analysis of randomized controlled trials. Crit Rev Oncol Melanoma. Clin Cancer Res. 2016;22(2):374-82. Hematol. 2010;73(3):220-7.

39.Zang Y, Dong M, Zhang K, et al. Hormonal therapy in uterine sarcomas. 40.Zhou WB, Ding Q, Chen L, Liu XA, Wang S. Toremifene is an effective and Cancer Med. 2019;8(4):1339-1349. safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials. Breast Cancer Res Treat. 2011;128(3):625-31.

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IHC thresholds Biomarker Negative Not Significant Positive AR ≤1+ or ≤10% Not applicable ≥1+ and ≥10% PD-L1 (22C3) TILs NA and 0% Not applicable ≥1+ and ≥50% PD-L1 (22C3) Tumor CPS < 10 Not applicable CPS ≥ 10 PD-L1 (SP142) IC ≤1+ and <1% Not applicable ≥1+ and ≥1% TP (TYMP) ≤1+ and ≤10% 1+ in 11-100% or 2+/3+/4+ in 1-29% ≥2+ and ≥30%

SAMPLE

Final Report Paradigm, an Exact Sciences company Laboratory Director: 1-844-232-4719 445 N 5th St., Phoenix, AZ 85004 Joshua Routh, MD Page 15 of 16 CLIA# 03D2082339 Patient Name Final Report Date Breast Cancer - Invasive Precision Female 01/01/2099

Performance Reimbursement and acknowledgment Biomarker Sensitivity Specificity Exact Sciences makes no representations or guarantee that an insurer, third party payor, or SNVs, Indels ≥ 7.5%: >99% >99% healthcare provider, whether private or governmental, will provide payment or reimbursement SNVs, Indels ≥ 5%: >97% >99% for the cost of tests performed. By accessing this report you agree that the analysis and CNV: >90% >99% associated report is owned by Exact Sciences and that you only have a limited right to use the information to potentially assist with the clinical treatment of the associated patient. Fusions: >91% >99% IHC: >94% >94% Pan-Cancer Tissue panel core components Limitations: Mutation calls may not be available from some regions due to Unless fewer tests are ordered on the requisition, every Pan-Cancer Tissue test run interrogates pseudogenes or sequence context. Select IHCs may not be run if already performed a wide panel of targets including the following clinically actionable genes for specific within the last six months unless indicated in the notes section. therapeutic interventions. Pan-Cancer Tissue tests are not intended to displace other specific standard of care tests for other gene targets. The BRCA1 and BRCA2 component is not These tests were developed and the performance characteristics determined by intended to diagnose or identify a hereditary condition, and mutations detected may be Exact Sciences. NGS is performed by Exact Sciences on genomic DNA extracted somatic or germline in origin and are to be used primarily for individualized therapeutic from a formalin fixed paraffin-embedded tumor. Immunohistochemistry: Detection: purposes while appropriate genetic counseling and testing may be advisable. IHC testing is done on formalin fixed, paraffin-embedded tissue (FFPE) utilizing the detection method of avidin-biotin free polymer is employed according to an optimized protocol. Scoring: HER2 testing meets the 2013 ASCO-CAP HER2 testing Levels of evidence guidelines in breast cancer and results are reported using the ASCO/CAP scoring criteria as defined in the references below. For ER and PR, historical cutoffs for all U.S. Preventive Services Task Force Level of Evidence Rankings are summarized from: non-breast tissues are followed. The following are antibody clones for each test: American journal of preventive medicine (2001), 20(3 Suppl), 21-35. Level of evidence doesn't HER2 - CB11, ER - SP1, PR - PgR636. Note that these assays have not been validated necessarily indicate greater potential utility. on decalcified specimens. Controls: External controls are reviewed on all stains for Level 1: Evidence from at least one properly designed randomized controlled trial. appropriate positive and negative immunoreactivity and found to be satisfactory. If Level II-1: Evidence from well-designed controlled trials without randomization. HER2 by FISH is run, it is currently performed and interpreted by PhenoPath at 551 Level II-2: Evidence from well-designed cohort or case- control analytic studies, preferably from N. 34th St., Seattle, WA 98103. If RNA Fusion testing is run, it is currently performed more than one center or research group. by PathGroup - Molecular Pathology Accessioning at 658 Grassmere Park, Suite 101, Level II-3: Evidence from multiple time series with or without the intervention. Dramatic results Nashville, TN 37211. in uncontrolled experiments (such as the results of the introduction of penicillin treatment in Pan-Cancer Tissue tests were developed and their performance characteristics the 1940s) could also be regarded as this type of evidence. determined by Exact Sciences. These tests have not been cleared or approved by the Level III: Opinions of respected authorities, based on clinical experience, U.S. Food and Drug Administration. These tests are used for clinical purposes to descriptive studies and case reports, or reports of expert committees. guide patient care under the responsibility of the physician. Different Tumor Type (DTT): Alteration in biomarker present, however published evidence of biomarker utility was in a tumor type different from patient's tumor type. 1. Wolff et al. (2013) J Clin Oncol. 31:3997-4013. 2. Hammond et al. (2010) Arch Pathol Lab Med. 134:48-72. 3. Tse, et al. (2011) J Clin Oncol. 29:4168-4174. No warranty or guarantee This report does not make any promise or guarantee that a particular drug or treatment Clinical trials regimen will be effective or helpful in the treatment of disease in any patient. This report also makes no promise or guarantee that a drug with a potential clinical benefit will in fact provide a The clinical trials information provided with the potential biomarker were compiled clinical benefit or that a drug with potential lack of clinical benefit will in fact provide no clinical from www.clinicaltrials.gov a service provided by the U.S. NIH. The presentation is for benefit. Exact Sciences expressly disclaims and makes no representation or warranties informational purposes only and may not include all relevant trials. Health care whatsoever relating, directly or indirectly, to this review of evidence or identified scientific providers should employ their clinical judgment in interpreting this information for literature, the conclusions drawn from it or any of the information set forth in this report that is individual patients. Specific enrollment criteria for each clinical trial should be derived from such review, including information and conclusions relating to therapeutic agents carefully reviewed as additional inclusion criteria may apply and the biomarker may that are included or omitted from this report. be associated with contraindications or exclusion criteria. The attending physician may need to contact the clinical trial administrator to ensure the patient is a possible This assay has not been validated on decalcified tissues. Results should be interpreted with candidate for admission to a particular clinical trial. caution given the possibility of false negative results on decalcified specimens.

NCCN compendium Treatment decisions

This report includes information about therapeutic agents that appear to be Treatment Decisions Reside with Treating Physician and Patient. The selection of any treatment associated with clinical benefit based on NCCN Compendium guidelines, relevance or potential treatment suggested by a biomarker resides within the discretion and judgment of of tumor lineage, level of publishing evidence and strength of biomarker expression, the treating physician and patient. Decisions on patient care should be based on the as available, as reviewed and assessed by Exact Sciences. The agents are not ranked independent medical judgment of the treating physician based upon all available clinical in order of potential or predicted efficacy. TheSAMPLE finding of a biomarker expression information, according to the applicable standard of care and should not be based solely on does not necessarily indicate effectiveness or lack thereof. The agents identified may the tests and information contained in this report. or may not be suitable for use with a particular patient and the report does not guarantee or suggest that any particular agent will be effective with the treatment of any particular condition.

Final Report Paradigm, an Exact Sciences company Laboratory Director: 1-844-232-4719 445 N 5th St., Phoenix, AZ 85004 Joshua Routh, MD Page 16 of 16 CLIA# 03D2082339